AU2008316315A1

AU2008316315A1 - A method and medicament for pain management

Info

Publication number: AU2008316315A1
Application number: AU2008316315A
Authority: AU
Inventors: Colin Dunlop
Original assignee: Individual
Current assignee: Individual
Priority date: 2007-10-24
Filing date: 2008-10-24
Publication date: 2009-04-30
Anticipated expiration: 2028-10-24
Also published as: GB2467266B; AU2008316315B2; WO2009052569A1; CA2711824C; US20170112784A1; GB201008606D0; US20110306676A1; GB2467266A; CA2711824A1

Description

WO 2009/052569 PCT/AU2008/001567 A METHOD AND MEDICAMENT FOR PAIN MANAGEMENT Field of the Invention 5 The present invention relates to a method and medicament for the treatment of pain and, particularly, but not exclusively, to a method and medicament for treating pain following a medical operation on a patient, such as surgery. 10 Background of the Invention Management of pain in patients is very important, particularly during and after treatment of a patient by is methods such as surgery. In animals, for example, pain can cause physical discomfort and stress resulting in high circulating catecholamines, increased vasomotor tone, hyperventilation 20 and hypoglycemia. Pain in animals can slow recovery from an operation and even cause more immediate problems post surgery when an animal may be "waking up" from surgery and experiencing pain. This may result in movements that may lead to complications and an extended period of recovery. 25 Pain alters behaviour including the quality of sleep, feeding and watering intake. All of these factors affect recovery from tissue injury or trauma. Pain is no less of an issue in humans who may be 30 recovering from trauma for tissue injury or following an operation such as surgery. Improved management of pain in veterinary and human applications may lead to improved quality of recovery from 35 trauma, such as surgery.

WO 2009/052569 PCT/AU2008/001567 -2 In general veterinary and/or human patient practice analgesic drugs are routinely given to surgical patients in the peri-operative period. In animals, the most commonly used analgesics includes systemic opioids, 5 NSAID's and local or regional nerve blockers. NSAID's such as Carprofen" or Metacam' are routinely administered before or during surgery and may be also for 24 to 36 hours post surgery. For major surgery, a variety of techniques are used including opioid, lignocaine and 10 ketamine infusions, local or regional blockers and fentanyl patches. Although these analgesic drugs are useful, it is believed that there exists room for improvement in pain management in veterinary and human treatments, and also room for providing alternative 15 analgesic treatments in order to provide more options for treatment. In recent years, in both animal and human medicine, there has been general movement away from longer acting 20 anaesthetic agents. There are a number of reasons for this, including occupational health considerations. Long acting anaesthetic agents such as methoxyflurane and many other inhalation anaesthetics have fallen out of favour for a variety of reasons, including environmental 25 toxicity. In laboratory animal anaesthesia, many university animal ethics committees actively discourage the use of anaesthetics with high metabolism or potential occupational health considerations, including methoxyflurane. Methoxyflurane has also been known to 30 cause renal problems in animals and humans. Fast acting anaesthetics, such as isoflurane or sevoflurane, can lead to problems during recovery. For example, when a horse recovers from anaesthesia, either 35 because of pain or the "shock" of waking, the horse will often try to stand, or move quite quickly after recovery and this may lead to injury. Horses are typically placed WO 2009/052569 PCT/AU2008/001567 -3 in recovery rooms with padded walls in order to minimise trauma on fast recovery from an anaesthetic. Other animals and humans may also experience problems during fast recovery from anaesthesia. 5 Physical discomfort and stress also occur during euthanasia of animals, particularly where numbers of animals are euthanized simultaneously using noxious inhaled gases such as CO 2 or carbon-monoxide. Pain and 10 stress to animals caused by such a procedure is unnecessarily cruel but also prolongs the time taken to cause death because stress increases cerebral stimulation and circulating catecholamines which cause redistribution of blood flow away from the vital organs where the noxious 15 agent causes its effect in a concentration dependent manner. Prolonged and agonal euthanasia is also undesirable from an occupational perspective because it adds additional pressure to workers already performing a high-stress job. 20 Summary of the Invention In accordance with a first aspect, the present invention provides a method of treating pain in a patient, 25 comprising the step of administering an inhalation anaesthetic at sub-anaesthetic levels to the patient during anaesthesia of the patient. In embodiments, suitable inhalation anaesthetics 30 include methoxyflurane, diethyl ether, trichloroethylene, chloroform,and others. The applicants have found that administering, for example, methoxyflurane at sub-anaesthetic levels can 35 produce affects on patients post-anaesthesia in relation to pain management. It is also thought that it may have an analgesic effect during anaesthesia. Pain may WO 2009/052569 PCT/AU2008/001567 -4 therefore be reduced or prevented during and post anaesthesia. An additional advantage is that because the methoxyflurane (or other inhalation anaesthetic) is used at sub-anaesthetic levels, the health effects associated s with methoxyflurane in use as an anaesthetic are reduced or avoided (eg renal problems, environmental toxicity). A further advantage of at least an embodiment is that methoxyflurane or other long acting inhalation anaesthetics like methoxyflurane, because they are long 10 acting, slow recovery from anaesthesia. Patients are likely to remain in a calm state for longer, therefore, because their pain is being managed and their recovery from anaesthesia is slow, reducing the chances of the patient causing themselves harm because of movements 15 brought on by rapid, painful recovery from anaesthesia. The inhalation anaesthetic may be administered during the entire period of anaesthesia or only part or parts of the period. In an embodiment, methoxyflurane or other 20 inhalation anaesthetic is administered towards or at the end of the anaesthesia. In an embodiment methoxyflurane is administered at any time during the peri-operative period. In some embodiments, methoxyflurane is administered before, during and/or after anaesthesia. 25 In an embodiment, the method comprises the further step of administering the inhalation anaesthetic post anaesthesia to maintain an analgesic effect. In an embodiment the inhalation anaesthetic administered post 30 anaesthesia is administered at sub-anaesthetic dosages. In an embodiment, where the inhalation anaesthetic is methoxyflurane, the dosages of methoxyflurane administered may be between 0.01 and 0.7 MAC (minimum alveoli 35 concentration). In an embodiment, the dosage is between 0.05 and 0.65 MAC. In an embodiment, the dosage is WO 2009/052569 PCT/AU2008/001567 -5 between 0.1 and 0.6 MAC. In an embodiment, the dosage is between 0.2 and 0.5 MAC. The applicants believe that methoxyflurane and other 5 long acting anaesthetics will exhibit an analgesic effect in patients for a relatively long period of time following anaesthesia, when administered at sub-anaesthetic levels. During anaesthesia, the inhalation anaesthetic, such 10 as methoxyflurane, may be used together with any anaesthetic. In an embodiment, the anaesthetic may be isoflurane, halothane, sevoflurane, desflurane, or any other anaesthetic (including all fast acting anaesthetics). 15 In one embodiment, the anaesthetic may be delivered at sub-anaesthetic levels to reduce pain during a euthanasia process, for example, for animals such as lab animals. The sub-anaesthetic doses may be delivered 20 together with a noxious agent such as CO 2 or carbon monoxide or other noxious agent. Advantageously, pain and stress is reduced prior to enduring euthanasia. The patient may be an animal patient and the method 25 may be applied in veterinary medicine. Alternatively, the patient may be a human patient, in human medicine. In accordance with a second aspect, the present invention provides use of an inhalation anaesthetic in the 30 manufacture of a medicament for the treatment of pain, wherein the medicament is administered at sub-anaesthetic levels in combination with an anaesthetic. The medicament may be administered during anaesthesia 35 of a patient, throughout the anaesthesia or at any time during anaesthesia, for example, towards the end of anaesthesia.

WO 2009/052569 PCT/AU2008/001567 -6 In an embodiment, the medicament is administered post-anaesthesia to maintain an analgesic effect. 5 The patient may be an animal patient or a human patient. In an embodiment, the inhalation anaesthetic is methoxyflurane. 10 In accordance with a third aspect, the present invention provides use of an inhalation anaesthetic in the manufacture of a medicament for the treatment of pain following surgery, wherein the medicament is administered 15 at a sub-anaesthetic dosage in combination with an anaesthetic during the surgery. The medicament may be administered throughout the surgery, or at any time during the surgery, for example 20 towards the end of the surgery. In an embodiment, the dosage is between 0.01 to 0.7 MAC. In an embodiment between 0.05 to 0.65 MAC. In an embodiment between 0.1 and 0.6 MAC. In an embodiment 25 between 0.2 and 0.5 MAC. In an embodiment, the inhalation anaesthetic is methoxyflurane. 30 In accordance with a fourth aspect, the present invention provides inhalation anaesthetic for use in the treatment of pain, wherein the inhalation anaesthetic is administered at a sub-anaesthetic dosage in combination with an anaesthetic. 35 The inhalation anaesthetic may be administered during anaesthesia in a patient. It may be administered WO 2009/052569 PCT/AU2008/001567 -7 throughout the anaesthesia. Alternatively it may administered at any time during the anaesthesia. In an embodiment, it is administered towards the end of the anaesthesia. 5 In an embodiment, the inhalation anaesthetic is also administered post-anaesthesia to maintain an analgesic effect. 10 In an embodiment, the dosage of the inhalation anaesthetic is between 0.01 to 0.7 MAC. In an embodiment between 0.05 to 0.65 MAC. In an embodiment between 0.1 and 0.6 MAC. In an embodiment between 0.2 and 0.5 MAC. 15 In an embodiment, the inhalation anaesthetic is methoxyflurane. In accordance with a fifth aspect, the present invention provides inhalation anaesthetic for use in the 20 treatment of pain following surgery, wherein the inhalation anaesthetic is administered at a sub anaesthetic dosage in combination with an anaesthetic during the surgery. 25 In an embodiment, the inhalation anaesthetic is administered throughout the anaesthesia during surgery. In an embodiment, the inhalation anaesthetic may be administered at any time during the surgery. In an embodiment it may be administered towards the end of the 30 surgery. In an embodiment, the inhalation anaesthetic is also administered post-anaesthesia to maintain an analgesic effect. 35 In an embodiment, the dosage of inhalation anaesthetic administered is between between 0.01 to 0.7 WO 2009/052569 PCT/AU2008/001567 -8 MAC. In an embodiment between 0.05 to 0.65 MAC. In an embodiment between 0.1 and 0.6 MAC. In an embodiment between 0.2 and 0.5 MAC. s In an embodiment, the inhalation anaesthetic is methoxyflurane. The patient may be a human or animal patient. 10 In accordance with a sixth aspect, the present invention provides a method of treating pain in veterinary applications, comprising the step of administering an inhalation anaesthetic at sub-anaesthetic levels to veterinary patients. 15 Inhalation anaesthetics such as methoxyflurane have the advantage of reducing or removing pain when administered at sub-anaesthetic levels. This facilitates pain management in veterinary patients that may have 20 undergone a trauma, for example an accident or surgery. The inhalation anaesthetic may be administered during surgery. It may be administered at the end of surgery. In an embodiment, the inhalation anaesthetic may be 25 administered after the surgery. In an embodiment, inhalation anaesthetic may be administered at any time to the animal patient in order to reduce or remove pain. 30 In an embodiment, the inhalation anaesthetic is administered before or during euthanasia. It may be administered along with a noxious gas or substance to deliver euthanasia. The use of the inhalation anaesthetic 35 advantageously decreases pain and stress before and during euthanasia.

WO 2009/052569 PCT/AU2008/001567 -9 In accordance with a seventh aspect, the present invention provides an apparatus for delivering sub-anaesthetic doses of inhalation anaesthetic for use in the treatment of pain during surgery, the apparatus s comprising a vaporiser for delivering the inhalation anaesthetic, and a vaporiser for delivering anaesthetic whereby the anaesthetic and inhalation anaesthetic are delivered in combination to the patient. 10 In an embodiment, the vaporiser for delivering the inhalation anaesthetic is in-circuit. In an embodiment, the vaporiser for delivering the anaesthetic for anaesthesia is an out of circuit 15 vaporiser. In an embodiment, it is a precision vaporiser. In an embodiment, the anaesthetic circuit is a closed circuit. 20 In an eighth aspect, the present invention provides a method of controlling recovery from an anaesthetic in a patient, comprising the step of administering an inhalation anaesthetic at sub-anaesthetic levels to the patient during anaesthesia of the patient. 25 In a ninth aspect, the present invention provides use of an inhalation anaesthetic in the manufacture of a medicament for controlling recovery from anaesthesia, wherein the medicament is administered at sub-anaesthetic 30 levels in combination with an anaesthetic. In a tenth aspect, the present invention provides inhalation anaesthetic for use in controlling recovery from anaesthesia, wherein the inhalation anaesthetic is 35 administered at a sub-anaesthetic dosage in combination with an anaesthetic.

WO 2009/052569 PCT/AU2008/001567 - 10 In an eleventh aspect, the present invention provides a method of treating pain before or during euthanasia in veterinary applications, comprising the step of administering an inhalation anaesthetic before or during 5 euthanasia, together with a toxic substance for euthanasia, to veterinary patients. In an embodiment, the inhalation anaesthetic is methoxyflurane. 10 Brief Description of the Drawings Features and advantages of the present invention will become apparent from the following description of 15 embodiments therefore, by way of example only, with reference to the accompanying drawing, in which the single figure is a diagram of an apparatus in accordance with an embodiment of the present invention for delivering an inhalation anaesthetic at a sub-anaesthetic dosage, in 20 combination with an anaesthetic. Details Description of Embodiments Embodiments of the present invention relate to the 25 management of pain and/or management of recovery from anaesthesia by the delivery of sub-anaesthetic levels of inhalation anaesthetic to a patient. The sub-anaesthetic levels of anaesthetic are delivered during anaesthesia, along with delivery of an anaesthetic to cause the 30 anaesthesia. The inhalation anaesthetic is used in these embodiments as an "adjunct to anaesthesia" to cause an analgesic effect in the patient. The use of inhalation anaesthetics as an adjunct to anaesthesia may also slow recovery from the anaesthetic, advantageously leading to a 35 gentler controlled recovery and a lower risk of the patient harming themselves because of a rapid recovery from anaesthesia.

WO 2009/052569 PCT/AU2008/001567 - 11 The term "sub-anaesthetic level" means a concentration or dosage of inhalation anaesthetic which is not sufficient to cause a state of anaesthesia. This 5 level will vary from patient to patient, but typically occurs at about 0.75 MAC. The surgical level of anaesthesia is typically 1.2 to 1.3 MAC. In the following described embodiment, the inhalation 10 anaesthetic used to deliver the analgesic effect/slow recovery from anaesthesia, is methoxyflurane. The present invention is not limited to the use of methoxyflurane. Other inhalation anaesthetics may be used at sub-anaesthetic levels to implement pain management/manage 15 recovery from anaesthesia. Suitable alternative substances to methoxyflurane may include diethyl ether, chloroform, trichlorothylene and others. Suitable properties for the inhalation anaesthetic include having high solubility, so that the anaesthetic will be dissolved 20 in the patient's tissues and persist for a relatively long time period, and having analgesic properties. The methoxyflurane treatment may be used for both animal patients and human patients who have undergone 25 trauma/surgery and who require a procedure which necessitates use of an anaesthetic. The methoxyflurane may be delivered in small amounts throughout the course of the anaesthesia (at any time during the peri-operative period). Because methoxyflurane is highly soluble in 30 tissues, the analgesic effects will persist for a relatively long period of time, in the order of 12 to 74 hours depending on the patient and the dosage. Methoxyflurane may be administered simultaneously 35 with the anaesthetic or sequentially with the anaesthetic.

WO 2009/052569 PCT/AU2008/001567 - 12 Alternatively, the dosage of methoxyflurane may be given at the end of or towards the end of the anaesthesia. Sufficient dosage is given to produce a persistent analgesic effect for a substantial time (12 to 74 hours, 5 for example) post anaesthesia. As well as delivering the methoxyflurane sub anaesthetic dose along with an anaesthetic during anaesthesia, following the procedure further sub 10 anaesthetic levels of methoxyflurane may be delivered to the patient in order to maintain the analgesic effect. The anaesthetic used with the methoxyflurane to bring about anaesthesia may be any anaesthetic. In this 15 embodiment the anaesthetic is an inhalation anaesthetic such as isoflurane, sevoflurane, halothane or desflurane (relatively fast acting inhalation anaesthetics). As discussed above, when methoxyflurane was used as a 20 general anaesthetic there were issues with occupational health and safety, and also renal problems as side-effects with large dosages (e.g. 8 or more MAC hours). Low-dose co-administration of methoxyflurane as an adjunct to anaesthesia, in accordance with this embodiment of the 25 invention, reduces these concerns. Further, simple anaesthesia equipment can be utilized, there is little risk of administration of a hypoxic mixture, occupational health considerations are minimized and waste anaesthetic gas may be easily managed. Advantages of methoxyflurane 30 include: e it can be scavenged in charcoal; e methoxyflurane is a potent compound, so small concentrations are effective; e it will provide intra-operative analgesia (as well as 35 post-operative analgesia) so there will be less "patient wake-up" during surgery, which will also lead to no increase in cost of the primary inhalation WO 2009/052569 PCT/AU2008/001567 - 13 anaesthetic (i.e. no increase in dosage of primary inhalation anaesthetic will be required to deal with patient wake-up problems); e co-administration of methoxyflurane as an adjunct to 5 anaesthesia with the primary anaesthetic (which in this embodiment is an inhalation anaesthetic such as isoflurane or sevoflurane) decreases the amount of primary inhalation anaesthetic required and therefore saves cost of expensive anaesthetics such as 10 isoflurane or sevoflurane; e duration of post-anaesthesia analgesia will depend on the concentration of methoxyflurane administered and the duration of administration, but is reasonably expected to be between 8 and 24 hours for a 1 to 2 is hour procedure; e the use of the methoxyflurane will slow recovery from the anaesthetic procedure, which means that sharp movements and patients damaging themselves by sharp, quick movements is less likely. This is particularly 20 important for animal patients. The drawing illustrates an apparatus in accordance with an embodiment of the present invention, which is arranged to facilitate administration of inhalation 25 anaesthetic in accordance with an embodiment of the present invention. In this embodiment the inhalation anaesthetic is methoxyflurane. The illustrated apparatus includes a delivery system 30 for delivering oxygen and anaesthetic (generally designated by reference numeral 1) to a patient (not shown) via a patient re-breathing circuit generally designated by reference numeral 2. A pressurised source of oxygen 3 is provided. Connected via a line 4 to the 35 source 3 is a regulator 5 for regulating oxygen pressure and a pressure gauge 6. An oxygen flow meter 7 is WO 2009/052569 PCT/AU2008/001567 - 14 connected in the line 4 from the regulator 5 to an anaesthetic vaporiser 8. In this example, the vaporiser 8 is arranged for the 5 delivery of the fast acting inhalation anaesthetic isoflurane. It will be appreciated that the present invention is not limited to any particular anaesthetic to be used in combination with the inhalation anaesthetic for analgesia. Isoflurane is one suitable anaesthetic, 10 sevoflurane is another, and there may be many others. It will depend on the procedure, the patient and the patient requirements. The line 4 connects the output of the vaporiser 8 to the patient re-breathing circuit 2, conveying a mixture of oxygen and isoflurane anaesthetic is to the patient re-breathing circuit 2. The re-breathing circuit 2 comprises a line 9 conveying the oxygen and isoflurane mixture, via in-circuit vaporiser 10 to a line 11 to the patient. A 20 mask or endotracheal tube (not shown) will usually be connected to the line 11 in order to deliver the anaesthetic oxygen to the patient. A return line 12 receives waste gases from the patient. These are conveyed via a vessel 13 which contains soda lime for removing 25 carbon dioxide from the waste gases so that the gases can be re-breathed. Non-return valves (not shown) ensure that gas flow direction in the re-breathing circuit 2 is one way. The re-breathing circuit 2 also includes a reservoir or re-breathing bag 14, which provides a variable storage 30 volume to compensate for variations in sizes of breath for each patient. It also allows for positive ventilation. A "pop-off" valve 15 is also provided for relieving pressure in the circuit if necessary. A pressure gauge 16 is provided to indicate the pressure in the re-breathing 35 circuit 2. A flush by-pass system is also provided (not shown in the diagram) in order to by-pass the vaporiser 8 WO 2009/052569 PCT/AU2008/001567 - 15 and provide pure oxygen to the circuit 2 on operation of a flush valve. In this embodiment, the in-circuit vaporiser 10 is 5 arranged to provide a controlled dose of methoxyflurane, at sub-anaesthetic levels, in order to provide an analgesic effect and optionally also slow recovery from the anaesthesia. As discussed above, the dosage will depend upon a number of factors, including the size of the 10 patient, the type of patient (e.g. animal, human, metabolic rate, etc.), the amount of time that the analgesia effect is required post-anaesthesia, the speed of recovery from anaesthesia that is required. In general, the amount of methoxyflurane dosage will be 1 between 0.01 and 0.7 MAC. In this embodiment it will be in the range of between 0.1 and 0.6 MAC. The above-described apparatus is one embodiment only of an apparatus for delivery of the inhalation anaesthetic 20 for the purposes of analgesia and/or to slow recovery from anaesthetic. Other methods of delivery and other arrangements for delivery may be utilised. For exampl-e, dual out-of-circuit precision vaporisers may be utilised, one for methoxyflurane and one for isoflurane or 25 sevoflurane (or other anaesthetic). Delivery may alternatively be by injection of the analgesic and/or the anaesthetic. Delivery may be by an inhaler and/or a mask. Delivery post anaesthetic, for 30 example, may be via an inhaler. There may be other methods of delivery that may be utilised. Example 35 Administration of methoxyflurane for a short period at the end of equine anaesthesia to modify recovery from isoflurane or sevoflurane.

WO 2009/052569 PCT/AU2008/001567 - 16 As in human medicine, complications can and do arise during anaesthesia and in the recovery period. Mortality rates in veterinary anaesthesia today range from 100 to 5 500 deaths per 100,000 anaesthetics for pet animals (cats and dogs) to 350 to 1,000 deaths per 100,000 anaesthetised horses. In horses, recovery to consciousness is a major cause 10 of anaesthesia-related morbidity and mortality, accounting for 50% of horse anaesthesia deaths. Because of their size and potential for injury, horses are typically placed in dimly lit, padded rooms to recover from anaesthesia. 15 At Randwick Equine Centre in Sydney halothane is routinely administered to 0.01 mg/kg acepromazine & methadone 0.05 mg/kg +/- xylazine 0.2 mg/kg all IM 15 minutes before the end of the procedure where there isconcerns about a poor recovery or a painful procedure 20 where the veterinary surgeon is unable to provide a local block to provide analgesia (eg throat sx). Halothane use is rapidly declining because of a lack of licensed manufacturers. Halothane has been widely used 25 because horses ventilate well during anaesthesia (so the anaesthetic level is stable) and because it is generally associated with a reasonable quality of recovery, albeit slow (30 to 75 minutes). Slow, reasonable quality recoveries are acceptable, although because the horses are 30 directly monitored at this time, usually by a veterinarian, this is expensive from a man-power perspective. Isoflurane or Sevoflurane are the anaesthetics being 35 used to replace halothane. Both drugs have faster uptake/distribution so recoveries are faster. This causes a short period; usually 15 to 20 minutes from the end of WO 2009/052569 PCT/AU2008/001567 - 17 anaesthesia where the horse will suddenly attempt to stand, may fall once or twice, and then be able to stand in a reasonably stable fashion. 5 Veterinarians are currently working to change to these newer agents and utilise various methods to modify recovery such as that described above at Randwick Equine Centre. Alternatively, infusions of short acting parenteral drugs such as propofol are being administered 10 for 10 to 15 minutes at the end of anaesthesia to keep the horse "asleep" to allow it to "blow off" the Isoflurane or Sevoflurane. Veterinarians in equine surgical practice desire a 15 simple method for improving the quality of recovery from equine anaesthesia (by prolonging the "sleep time"). Example: Trial of methoxyflurane administered to horses at the 20 end of anaesthesia, attempting to modify recovery: On 12 different days MOF was administered to 12 horses at the end of between 1 to 2 hours of isoflurane anaesthesia with the intention of improving the quality of 25 recovery from anaesthesia by slowing the recovery time. Horses recovering from isoflurane typically attempt to stand in 10 to 15 minutes, usually fall down and try to get back up 2 or 3 times (sometimes violent, resulting in injuries from skin abrasions to fractured limbs) and are 30 then standing 15 to 20 minutes after anaesthetic administration ceased. In comparison, halothane results in slower recoveries, typically twice as long as isoflurane. Halothane recoveries are less violent and result in less likelihood of injury. 35 Initially trials were also performed in anattempt to determine the dose and duration of MOF administration that WO 2009/052569 PCT/AU2008/001567 - 18 would result in improved quality of recovery. The trials showed that the MOF dose required was much lower and the duration of MOF administration much shorter than anticipated. The initial trials resulted in long 5 recoveries with marked ataxia, in some cases resulting in minor injury to the horse. The last 8 horses were administered with ever lower doses of MOF for less time with better results (see table 10 below). There was less ataxia and a better quality recovery although the dose was decreased up until the last horse. The lowest dose produced a good result. Wt Anaesth Methoxy 1" Stem. Stnd Atax Walk Comments kgs duration Movt out Mins. Total ml 472 130 ISO 23 32 63 78 .100 Try stand at 23 min & fell 492 75 ISO 540 50 60 75 85 100 Stood 69- fell down x 2 470 85 ISO 210 5 14 29 35 55 lOx wobble then saw horse 338 30 HAL 27 30 31 Fell 55 Stood/fell x 3 then stall walk 462 135 ISO 350 48 ND 49 59 75 Still 45 mm then stood 492 90 HAL 30 50(2) 65 75 85 Poor - flip over 15 mm 580 160 ISO 300 37 60 61 85 90 Broke out of recov wreck 332 135ISO 200 17 25 26 30 41 Good is In addition to slowing recovery, methoxyflurane has the further advantage of providing an analgesic effect for a substantial amount of time after recovery from anaesthesia. 20 In the above embodiments inhalation anaesthetic is used during surgery. The present invention is not limited to be used during surgery, but may be used in any process where anaesthesia is required.

WO 2009/052569 PCT/AU2008/001567 - 19 As also discussed above, the present invention is not limited to the use of methoxyflurane as the inhalation anaesthetic. Other suitable inhalation anaesthetics could 5 be used. In another embodiment, the use of inhalation anaesthetic at sub-anaesthetic doses or even at anaesthetic doses may be used during or prior to 10 euthanasia using a noxious substance such as a noxious inhaled gas such as CO 2 or carbon monoxide. This may reduce pain and stress to animals caused by such a procedure. 15 Euthanasia of groups of animals together such as laboratory rats and mice, chickens for disease outbreak control and non-domestic cats at animal control centres, usually involves placing the animals in a chamber and administering a toxic and/or a noxious gas such as CO 2 or 20 carbon monoxide. Traditionally, these noxious agents are administered alone or with small amounts of air (e.g. 20% to prevent death by asphyxia, which is very stressful) despite our knowledge that such deaths appear to be associated with discomfort and/or pain to the animals. 25 Induction of anaesthesia with some inhalation anaesthetic agents such as methoxyflurane advantageously may be stress and pain free. In this embodiment, methoxyflurane or another 30 inhalation anaesthetic is delivered during or prior or both prior and during administration of toxic or noxious gases to animals being euthanized. It may be delivered to animals being euthanized in chambers. In an embodiment, the inhalation anaesthetic it administered with air or 35 oxygen at sub to anaesthetic levels to provide algesia, sub-anaesthesia (sedation) or anaesthesia, prior to administration of lethal concentrations of toxic or WO 2009/052569 PCT/AU2008/001567 - 20 noxious gases that will cause death. In this embodiment, the anaesthetic administration is of short term, sufficient to reduce stress during the actually euthanasia caused by a separate noxious gas. The anaesthetic drug of 5 itself could be administered at high concentration to cause death but it would be a slower process, not as reliable, cause significant environmental pollution and potentially occupation exposure or potential for abuse. 10 In another embodiment, there is simultaneous administration of the anaesthetic agent in an air or oxygen mixture with the noxious gas. For this embodiment, a less soluble (faster acting) inhalation anaesthetic is required, such as sevoflurane, isoflurane or possible 15 halothane. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary 20 implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. 25 It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments 30 are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. A method of treating pain in a patient, comprising the step of administering an inhalation s anaesthetic at sub-anaesthetic levels to the patient during anaesthesia of the patient.

2. A method in accordance with Claim 1, wherein the step of administering the inhalation anaesthetic is 10 carried out throughout anaesthesia.

3. A method in accordance with Claim 1, wherein the step of administering the inhalation anaesthetic is carried out towards the end of anaesthesia. 15

4. A method in accordance with Claim 1, 2 or 3, comprising a further step of administering the inhalation anaesthetic post-anaesthesia to maintain an analgesic effect. 20

5. A method in accordance with any one of the preceding claims, wherein the dosage of the inhalation anaesthetic administered is between 0.01 and 0.7 MAC. 25

6. A method in accordance with Claim 5, wherein the dosage is between 0.05 and 0.65 MAC.

7. A method in accordance with Claim 6, wherein the dosage is between 0.1 and 0.6 MAC. 30

8. A method in accordance with Claim 7, wherein the dosage is between 0.2 and 0.5 MAC.

9. A method in accordance with any one of the 35 preceding claims, wherein the patient is an animal.

10. A method in accordance with any one of Claims 1 WO 2009/052569 PCT/AU2008/001567 - 22 to 8, wherein the patient is a human.

11. A method in accordance with any one of the preceding claims, wherein the inhalation anaesthetic is 5 methoxyflurane.

12. Use of an inhalation anaesthetic in the manufacture of a medicament for the treatment of pain, wherein the medicament is administered at sub-anaesthetic 10 levels in combination with an anaesthetic.

13. Use of an inhalation anaesthetic in accordance with claim 12, wherein the inhalation anaesthetic is methoxyflurane. 15

14. Use of an inhalation anaesthetic in the manufacture of a medicament for the treatment of pain following surgery, wherein the medicament is administered at a sub-anaesthetic dosage in combination with an 20 anaesthetic during the surgery.

15. Use of an inhalation anaesthetic in accordance with claim 14, wherein the inhalation anaesthetic is methoxyflurane. 25

16. Inhalation anaesthetic for use in the treatment of pain, wherein the inhalation anaesthetic is administered at a sub-anaesthetic dosage in combination with an anaesthetic. 30

17. Inhalation anaesthetic in accordance with Claim 14, wherein the inhalation anaesthetic is methoxyflurane.

18. Inhalation anaesthetic for use in the treatment 35 of pain following surgery, wherein the inhalation anaesthetic is administered at a sub-anaesthetic dosage in combination with an anaesthetic during the surgery. WO 2009/052569 PCT/AU2008/001567 - 23

19. Inhalation anaesthetic in accordance with Claim 18, wherein the inhalation anaesthetic is methoxyflurane. s

20. Inhalation anaesthetic for use in a method in accordance with any one of Claims 1 to 11.

21. A method of treating pain in veterinary applications, comprising the step of administering 10 inhalation anaesthetic at sub-anaesthetic levels to veterinary patients.

22. A method in accordance with claim 21, wherein the inhalation anaesthetic is methoxyflurane. 15

23. A method of slowing recovery from an anaesthetic in a patient, comprising the step of administering an inhalation anaesthetic at sub-anaesthetic levels to the patient during anaesthesia of the patient. 20

24. A method in accordance with claim 23, wherein the step of administering the inhalation anaesthetic -is carried out towards the end of or at the end of anaesthesia. 25

25. A method in accordance with claim 23 or claim 24, wherein the inhalation anaesthetic is methoxyflurane.

26. Use of an inhalation anaesthetic in the 30 manufacture of a medicament for controlling recovery from anaesthesia, wherein the medicament is administered at sub-anaesthetic levels in combination with an anaesthetic.

27. Use of an inhalation anaesthetic in accordance 35 with claim 26, wherein the medicament is administered towards the end of or at the end of anaesthesia. WO 2009/052569 PCT/AU2008/001567 - 24

28. Use of an inhalation anaesthetic in accordance with claim 26 or claim 27, wherein the inhalation anaesthetic is methoxyflurane. 5

29. Inhalation anaesthetic for use in controlling recovery from anaesthesia, wherein the inhalation anaesthetic is administered at a sub-anaesthetic dosage in combination with an anaesthetic. 10

30. Inhalation anaesthetic in accordance with claim 29, wherein the inhalation anaesthetic is administered towards the end or at the end of anaesthesia.

31. Inhalation anaesthetic in accordance with claim 15 29 or claim 30, the inhalation anaesthetic being methoxyflurane.

32. An apparatus for delivering sub-anaesthetic doses of an inhalation anaesthetic for use in the treatment of 20 pain during surgery, the apparatus comprising a vaporiser for delivering the inhalation anaesthetic and a vaporiser for delivering anaesthetic, whereby the anaesthetic and inhalation anaesthetic are delivered in combination to the patient. 25

33. A method of treating pain before or during euthanasia in veterinary applications, comprising the step of administering an inhalation anaesthetic before or during euthanasia, together with a toxic substance for 30 euthanasia, to veterinary patients.

34. A method in accordance with claim 33, wherein the inhalation anaesthetic is methoxyflurane. 35